Powdered inhalants, as prepared according to the prior art (for example DE-A-179 22 07), in addition to the chemical stability of the active substance and the composition of the medicament as such must above all have physically constant properties. This means specifically that the aerosol properties must remain constant in terms of their aerodynamic characteristics (e.g. aerodynamic particle size). This means that both for the micronised active substance and for the excipients used in the product the latter should be used in their most physico-chemically stable form. For lactose, this means, from a thermodynamic point of view, that this is true when it is in the form of alpha-lactose monohydrate under normal conditions. This is particularly true of the crystalline ordering of the surface of the particles.
It is known that when organic substances are ground, as a result of the significant input of mechanical energy, amorphous fractions may be produced or there may be changes in the crystalline structure leading to thermodynamically less stable modifications. It is also known that lactose may occur in various forms (Coenraad F. Lerk, Physikalisch-pharmazeutische Eigenschaften von Lactose, Pharmazie in unserer Zeit, 16, 1987, No. 2; 39-46).
For example amorphous lactose produced during the grinding of lactose or under other mechanical stress may be recrystallised by known technical methods (e.g. WO 92/18110 or WO 95/05805). However, these methods have the drawback that they only achieve breakdown of amorphous fractions such as occur after micronisation processes. However, these processes do not necessarily result in the breakdown of beta-lactose, which may also occur in these treatment processes, and during the large-scale industrial grinding of lactose to a particle size range with a value of x50>10 μm. Thermodynamically unstable fractions such as beta-lactose, for example, even if they are only present on the surface of lactose, constitute a factor which may have a negative effect on the long-term and storage stability of an inhalable powder, for example.
The aim of the present invention is therefore to provide a process by which any thermodynamically less stable lactose fractions present, particularly fractions of beta-lactose, on the surface of crystalline lactose may be converted into alpha-lactose.
The detection of beta-lactose, for example on the surface of crystalline lactose, is analytically challenging, particularly when the amounts of beta-lactose are small.
The present invention therefore also sets out to provide a method of analysis which makes it possible to detect tiny amounts of beta-lactose in lactose crystals consisting predominantly of alpha-lactose.